Optimization of Novel NR2C and NR2D subunit-selective NMDA receptor potentiators

描述（由申请人提供）：精神分裂症是一种慢性神经系统疾病，其影响约1%的世界人口，仅在美国就造成> 600亿美元的直接和间接社会成本（Wu等人，2005年）的报告。目前治疗这种疾病的疗法 有效改善阳性症状（幻觉，妄想，非理性恐惧）， 但在控制阴性症状（社交退缩、快感缺乏）和认知功能障碍（学习和社交认知减少）方面效果较差。此外，目前许多抗精神病药物可引起锥体外系副作用（EPS）、代谢综合征（体重增加）和心血管风险增加。由于不能用今天的药物来控制精神分裂症的症状谱，精神分裂症仍然是一个严重的医学问题，需要确定药物干预的替代靶点。 谷氨酸受体功能减退已成为一种假说，以更充分地了解和治疗精神分裂症。这一假设最初是基于观察到N-甲基-D-天冬氨酸（NMDA）受体通道阻滞剂，如苯环己哌啶（PCP）可以诱导一种与人类和动物模型中精神分裂症的某些特征难以区分的心理状态。因此，NMDA受体功能的增强已经成为治疗精神分裂症的一个有吸引力的假设。最近，鉴定了小分子CIQ，（3-氯苯基）（6，7-二甲氧基-1-（（4-甲氧基苯氧基）甲基）-3，4-二氢异喹啉-2（1H）-基）甲酮，其选择性地将含有NMDA受体的GluN 2C和GluN 2D增强2倍。GluN 2C和GluN 2D亚基是特别感兴趣的靶标，因为它们在前脑中的表达谱是 主要限于海马和皮层中间神经元的子集，并且基于电路的精神分裂症模型预测GluN 2C/2D选择性增强剂驱动的中间神经元活性的增强可能特别有效。基于这些最新的研究结果，我们建议发现和开发新的GluN 2C/2D选择性增效剂，用于治疗精神分裂症的抗精神病药物。

DESCRIPTION (provided by applicant): Schizophrenia is a chronic neurological disorder that affects approximately 1% of the world population and causes > $60 billion dollars of direct and indirect societal costs in the US alone (Wu et al., 2005). Current therapies to treat this disorder have been effective in ameliorating positive symptoms (hallucinations, delusions, irrational fear), but are less effective in controlling negative symptoms (social withdrawal, anhedonia) and cognitive dysfunction (diminished learning and social cognition). Furthermore, many of the current antipsychotics can cause extrapyramidal side effects (EPS), metabolic syndrome (weight gain), and increased cardiovascular risk liabilities. Due to the inability to control the fll spectrum of symptoms with today's medicines schizophrenia remains a serious medical problem requiring the identification of alternative targets for pharmacological intervention. Glutamate receptor hypofunction has emerged as an hypothesis to more fully understand and treat schizophrenia. This hypothesis was based initially upon observations that N-methyl-D-aspartate (NMDA) receptor channel blockers such as phencyclidine (PCP) can induce a psychological state indistinguishable from some features of schizophrenia in man and in animal models. Thus, augmentation of NMDA receptor function has emerged as an attractive hypothesis as a therapy for schizophrenia. Recently, a small molecule CIQ, (3- chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1 H)-yl)methanone) was identified that selectively potentiates GluN2C and GluN2D containing NMDA receptors by 2-fold. GluN2C and GluN2D subunits are targets of particular interest in that their expression profile in forebrain is limited largely to a subset of hippocampal and cortical interneurons and that circuit-based models of schizophrenia predict that enhancement of interneuron activity driven by GluN2C/2D selective potentiators may be particularly efficacious. Based on these recent findings, we propose to discover and develop novel GluN2C/2D selective potentiators for use as antipsychotics in the treatment of schizophrenia.